This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A cohort of 8 monkeys infected as neonates or adults with a live attenuated simian immunodeficiency virus (SIV) 8 years ago represents long-term non-progressors (LTNP). These monkeys harbor a multiply deleted SIV, in which Rev and the Rev-Responsive Element (RRE) were replaced with the constitutive transport element (CTE) of simian retrovirus type D. The resulting Rev-independent nef-deleted SIV, termed Rev-ind nef[unreadable]SIV, critically depends on CTE for viral RNA export into the cytoplasm. Even monkeys infected as neonates controlled this virus, have no signs of immune dysfunction, and have persistent humoral and cellular SIV-specific immune responses. We are in the process of evaluating the degree of protection provided by Rev-ind nef[unreadable]SIV against low-dose mucosal challenges with pathogenic SIV. The LTNP received a high-dose intravenous boost of Rev-ind nef[unreadable]SIV;in parallel, 4 na[unreadable]ve controls were inoculated which became a chronically infected cohort. After the initial acute infection, viral loads became undetectable. None of the LTNP had measurable viremia post-boost. We are testing if protection depends on the time interval between infection with live attenuated virus and challenge with pathogenic virus;we are probing for any correlation between the degree of protection and parameters of innate and adaptive immunity. Time intervals studied included challenge of LTNP with a 7+-year history in chronic infection with the live attenuated virus, challenge during the chronic phase (about one year of infection with the live attenuated virus), and challenge during the acute infection. Challenge was performed with a heterologous strain of SIV that was clearly distinct form the vaccine strain. Our studies are significant because they have deepened our understanding of the host-virus dynamics in the LTNP and more closely mimic the mucosal HIV transmission in humans. We will continue to look for any correlation between the degree of protection and parameters of systemic and mucosal immunity.